Acute lymphoblastic leukemia (ALL) is fatal in approximately 15-20% of children and about 60% of adults. Moreover, therapy remains non-specific, morbid and sometimes life-threatening. We believe that improved outcomes will originate from laboratory investigation of the biology of ALL, leading to more specific therapies with less harmful effects of treatment. Project 1 will complete a genome-wide scan for mutations in tyrosine kinases in adult and childhood ALL to identify novel mutations that might serve as therapeutic targets for small molecule inhibitors. Project 2 will model the pathogenesis of TEL/AML1 leukemia in a mouse and test candidate activated tyrosine kinases and other small molecules in an in vivo assay system for inhibitors of TEL/AML1. Project 3 will utilize our zebrafish model of T-ALL to conduct forward genetic modifier screens for mutations that enhance or suppress the onset of the malignant phenotype. These mutations will be analyzed to discover new tumor suppressor pathways and new potential drug targets of human T-ALL. Project 4 will utilize chemical genomics to identify and screen small molecules capable of modulating relevant gene expression programs, such as the TEL/AML1, MLL and glucocorticoid resistance pathways. Project 5 will investigate the core pathway controlling glucocorticoid-induced apoptosis so that its modulation can be exploited as a potential therapeutic avenue. Finally, Project 6 will aim to maximize the therapeutic index in the treatment of ALL by reducing morbidity associated with current therapy, extending the successful pediatric regimen to an adult population, and during this funding period integrate biologic findings into clinical investigations of relapsed and refractory disease. With the inclusion of patients aged 1-50 years, we have the unique opportunity to directly compare uniformly treated adults and children in terms of response to therapy, toxicities, and underlying biology, potentially identifying age-independent targets for novel therapies. By understanding the pathogenesis and pathophysiology of ALL, manipulating potential targets, and translating laboratory findings in the context of clinical trials, we seek to improve outcome for patients with ALL, regardless of age, and to provide a model to stimulate similar advances in other diseases.